Data from a recent paper in European Urology has further confirmed the value of active surveillance as a first-line management option for men diagnosed with low-risk prostate cancer. It has also confirm recent guidance for when men on active surveillance actually need to be advised that treatment is probably wise.

This new paper by Bokhort et al. is based on data from the Prostate Cancer Research International Active Surveillance (PRIAS) study, which was started about 12 years ago in Europe to evaluate the optimal selection and follow-up processes for men on active surveillance (AS). The current paper reports data at the 10-year follow-up period.

PRIAS enrolled men with low-risk prostate cancer who were initially followed with regular PSA tests, digital rectal examinations, and biopsies. In the beginning, all men with a Gleason score of > 3 + 3, or more than two positive biopsy cores, or a clinical stage higher than cT2, or a PSA doubling time of < 3 years were advised to switch to active treatment. After 2014, the PSA doubling time criterion was modified (see below).

Here are the basic study findings:

PRIAS enrolled 5,302 men from 18 different countries.

Reclassification rates remained stable on all subsequent biopsies.

22 to 33 percent of men had either Gleason > 3 + 3 or more than two positive cores on any repeat biopsy.

At 5 and 10 years of follow-up, 52 and 73 percent of men, respectively, had discontinued active surveillance (most because of protocol-based reclassification).

A third of men undergoing radical prostatectomy continued to have favorable, post-surgical pathologic tumor features (Gleason 3 + 3 and pT2).

Of the criteria initially used to recommend a switch to active treatment, having three or more positive biopsy cores or having a PSA doubling time of < 3 years were not predictive of unfavorable pathologic outcome on radical prostatectomy.

The last two statements mean that a third of all the patients who came off active surveillance and received treatment based solely on having three or more positive biopsy cores or a PSA doubling time of < 3 years were being treated unnecessarily and could have remained on active surveillance (at least for a while).

Bokhorst et al. state clearly that, because, in this very large study, many men on active surveillance who were initially being advised to have treatment showed no signal for the necessity for that treatment based on their post-surgical pathology:

… we propose Gleason upgrading and cT3 as the only indicators for an immediate switch to active treatment. Surrogate indicators (e.g., more than two positive cores and a fast-rising PSA) should not trigger immediate active treatment but rather further investigation to confirm the suspicion of higher risk disease.

In a patient-specific summary, they also write that:

We confirmed the safety of active surveillance as a treatment option for men with low-risk prostate cancer; however, some changes could be made to the follow-up protocol to safely increase the number of men who remain on active surveillance.

These data come from by far the largest active surveillance study published to date, and they confirm what some patient advocates had believed for years — that many in the urology community had been overly cautious in their early recommendations as to when men on active surveillance should be advised to have treatment. The recommendations coming from the PRIAS investigators conform relatively closely to the recommendations that Klotz and the Sunnybrook group in Ontario, Canada, have already been following for some time. We would also emphasize that current NCCN guidelines go even further (as does the Sunnybrook group) in stating that continued active surveillance remains an option for selected men who are upgraded to Gleason 3 + 4 = 7, based on criteria such as their age, their PSA level, and other factors.

We can use the Memorial Sloan-Kettering Cancer Center male life expectancy survey to substantiate the wisdom of these revised recommendations, as follows:

Imagine a man who was 58 years of age at diagnosis with low-risk prostate cancer in 2010 (with a PSA of 3.8 ng/ml, a clinical stage of T1c, a Gleason score of 3 + 3 = 6, and two positive biopsy cores out of 12, both of which are 5 percent positive for cancer). If we assume that this patient is otherwise in excellent health, the life expectancy survey tells us that, 10 years after his diagnosis, i.e., by 2020, he would have < 1 percent (effectively zero) risk for prostate cancer-specific death.

Fast forward to today, in 2016. He is now 64 years of age. At his third follow-up biopsy after his initial diagnosis he has a PSA of 4.8, a clinical stage of T1c, a single focus of Gleason 3 + 4 prostate cancer and two other small foci of Gleason 3 + 3). The core that is positive with Gleason 3 + 4 = 7 is still only 5 percent positive, and of that positive tissue only 10 percent is Gleason pattern 4 (i.e., 0.5 percent of the entire positive core). Otherwise, our imaginary patient is still in excellent health.

The life expectancy survey now tells us that after another 10 years on active surveillance with no treatment (i.e., by 2026) he has a 6 percent risk for dying of prostate cancer and that after another 15 years on active surveillance with no treatment (i.e., by 2031, when he will be 79 years of age) he has a 12 percent risk of dying of prostate cancer. (At the same 15-year time point, he also has a 31 percent chance of being dead of something else altogether.)

But remember … this patient is on active surveillance …. He and his physicians can decide to intervene with active treatment at any time they choose. This patient may indeed need curative treatment at some time between 2016 and 2031, or he may not if his disease remains stable over the next 15 years. But at any time point along this journey the probability is extremely high that if active treatment is administered with curative intent, it will be successful in eliminating a localized form of prostate cancer. Why intervene any earlier than is absolutely necessary?

And one more thing, if this patient has the same data in 2016, with a single exception, which is that his Gleason scores for the three positive cores are all 3 + 3 = 6, then the life expectancy survey tells us that his risk of dying of prostate cancer is still effectively zero by 2026 and only 2 percent by 2031.

Now let us be very clear indeed. Living with the knowledge that one has a low-risk prostate cancer and deciding to “do nothing” on active surveillance may be either difficult or impossible for many men. We are not stating, and we do not intend to imply, that every man with low-risk prostate cancer should (let alone must) initially be on active surveillance. On the other hand, we are stating and we do mean to imply that every man diagnosed with low-risk prostate cancer should (and yes, must) be very clearly advised that active surveillance is a very reasonable first-line management option, even though treatment is certainly going to be necessary later for a significant percentage of such patients. To not so advise a man with low-risk prostate cancer today is both medically unethical and morally reprehensible (in our very humble opinion).

2 Responses

Thank you for posting this article. I have been on AS since August 2012, however, the most recent biopsy shows a positive core that is Gleason 6 and that the MRI stated as having minimal extraprostatic extension. So, with three biopsies behind me with a total of six positive cores, bilateral, and with maximum of 20% involvement, based on this article, I should continue to stay on AS. However, with the location of my recently found lesion at the left posterolateral peripheral apex, I am now evaluating active treatment.

While the study focused on the Gleason scores to determine the aggressiveness of the prostate cancer, it did not mention how the location of the positive lesion, regardless of it’s aggressiveness, should influence the decision to start active treatment.

Actually the study is very clear about the effect of clinical staging on the need for treatment (in the opinion of the study’s authors).

The article says that a man with clinical stage T3 disease or higher should probably have treatment as opposed to staying on active surveillance. If you have extraprostatic extension of any type, then you have at least T3a disease and should consider active surveillance. However, in the end, the decision as to whether you wish to be treated or to stay on active surveillance in a situation like yours is a very personal one and depends on all sorts of other factors in addition to your Gleason score and your clinical stage.

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